Prolonged release oral pharmaceutical preparations



iinited rates This invention relates to pharmaceutical preparationsproviding a prolonged release of the medicament.

The administration of drugs orally has presented a serious problem. Invery many cases, it is necessary for the drugs to be absorbed from thegastrointestinal tract into the bloodstream. When a drug is given bymouth, the assimilation is normally fairly rapid and presently the levelin the blood reaches a maximum. Then it declines as the drug is excretedor otherwise removed from the bloodstream. The blood level falls andfinally reaches a level so low that it is no longer effective and it isthen necessary to take, orally, another dose. The peaks and valleys thuscaused in blood level have several disadvantages. One is the necessityof taking frequent small doses in order to maintain a therapeuticallydesired blood level. This is awkward and in some instances presents aserious problem as the patient has to be awakened during the night totake further doses. A second drawback is that in order to have atherapeutically useful blood level, each dose has to be fairly large sothat after the blood level peak is reached and begins to subside, therewill still remain sufficient of the drug to be useful. The necessity forlarge doses brings with it some dangers. Nearly all drugs have someundesirable or toxic side effects when administered in sufficientlylarge doses and the large initial doses may be unacceptable or mayproduce some undesirable side reactions.

For the reasons set out above, various attempts have been made to slowup the release of drugs taken orally, producing a so-called prolongedrelease product. Sometimes it is felt desirable only to slow up therelease sufficiently so that it extends over a long enough time to evenout the more marked peaks and valleys in blood level. In other cases, itmay be desirable to prevent assimilation from the stomach but to permitassimilation from the intestine. Various coatings have been developed,the so-called enteric coatings, to achieve this purpose. The presentinvention constitutes an improved method of prolonging the release ofpharmaceuticals taken orally. In the past, a number of methods have beenused. A common one is to incorporate a number of so-called seeds ofdrugs in a single capsule. These seeds are small, spherical nuclei ofinert material, coated with the drug and finally over-coated withvarying amounts of slowly digestible fats with or without dispersiblewaxes which act as plasticizers. In the digestive tract, the seeds withno wax coating dissolve rapidly and produce the desired initial bloodlevel. Those with coatings more or less thick digest slowly andgradually set the drug free. There is a serious problem in obtaining theright proportion of seeds with the right thicknesses of digestiblecoatings and the fact that the medicament is coated on inert carriersreduces its content in a particular capsule. With drugs that are used invery small amounts, this latter fact may not be serious, but where thedose is to be substantial, a much larger capsule is needed or it isnecessary to ingest a larger number of capsules. It is also relativelyexpensive to produce the seeds with the varying coatings and thissolution to the problem, though useful, leaves much to be desired.

Another method lies in incorporating the desired medicament in a moltenmedium of the fats and/ or waxes aterit 3,9782% Patented Feb. 19, 1983which are slowly digestible or dispersible. The mixture is then cooledforming a cake which is broken up into suitable granules and tablettedor encapsulated. This method gives only an average rate of release.

In the case of drugs capable of adsorption on ion exchange resins, thedrugs can be adsorbed on such resins. Alternately, many drugs can beincorporated with plastics from which the digestive juices granduallyset free or leach out the medicament. These solutions are not usefulwhere it is necessary to have some of the drug released rapidly but giveonly an average, slow release. They are far inferior to the seed methodand involve just as much or more waste volume of inert material.Finally, another technique has involved the formation of a complex saltof the drug which is not assimilated in its complexed form but is slowlyhydrolyzed in the digestive tract and is set free gradually. This isapplicable, of course, only to certain drugs that are capable ofcomplexing and again it does not provide for rapid release of a portionof the drug to build up rapidly a satisfactory blood level, theso-called attack dose." The present invention solves the problems ofprolonged release with complete flexibility in rate and with thepossibility of making available sufiicient drug for rapid release togive a satisfactory attack dose.

Essentially, the present invention involves granulating the drug, or ifit is available in powder form already providing a definite range ofparticle sizes between predetermined limits, using it as such. Thesemixtures of granules or particles of different sizes are then coatedwith a slowly digestible coating of waxes and/0r fats. I have found,surprisingly, that the thickness of coating varies directly with thesize of the particle. The small particles have very thin coatings andthe larger particles have progressively thicker coatings in directproportion to the particle size. After coating, the particles of randomsizes or of a predetermined size range, with the corresponding variationin coating thicknesses, are then assembled into the final dosage unit.They may, for example, be filled into a capsule or they may becompressed into a tablet. If desired, the capsule or the tablet may beprovided with an enteric coating if it is desired that release of thedrug take place only in the intestinal tract, which is of importancewith certain drugs which are destroyed by the stomach acids. Anaccurately reproducible release rate can be obtained exctly suited forthe particular drug in question. For example, a slowly excreted drug mayhave a relatively large proportion of very small particles which releasetheir medicament rapidly to produce the necessary attack dose. In thecase of other drugs which are very rap-idly excreted or removed from thebloodstream, the proportion of very small particles is decreased so thatthe release is more uniform with time. Inasmuch as the rate of releasefrom any particle or granule is determined by the wax content of thecoating, which is a function of particle size, it is possible to producetablets, capsules, or other dosage forms having exactly the desiredprolonged release characteristics. At the same time, there is relativelylittle inert material, such as the cores of the so-called seedsdescribed above or the plastic or resin used in some of the othermethods. Except for the dispersible or digestible coating itself, thetablet or capsule can contain the drug but little diluted with inertmaterial, such inert material, in the form of binder, rarely exceeding5% of the total. It is thus possible in a small tablet or capsule toaccommodate a dose that would require a much bigger capsule or tablet ormany small ones in the case of other methods in which there is a largeamount of inert material present.

While the present invention is not limited to any particular process, ina more specific aspect an improved process is also included. Accordingto this process, fats and/or waxes for the coating are dissolved in avolatile solvent which need only be of sufiiciently low toxicity so thatminute residues do not present any toxic problem. One of the best ofsuch solvents is 1,1,l-trichlorethane, but the invention is not in anyway limited to this particular solvent. The particles of non-uniformsize are then coated by conventional means such as by spraying thesolution of fats or waxes onto the particles. At the same time, asufficient amount of air is passed through the equipment so that thesolvent rapidly volatilizes producing a firm coating almost instantly.The temperature of the individual particles should be between that atwhich the coating material is a hard solid and that at which it isliquid. This is important because if the temperature is too low,non-continuous coating may result which may to a greater or lesserextent defeat the object of the prolonged release by allowing digestivefluids to penetrate through the discontinuities. It is equallyundesirable to maintain the temperature high enough so that the fats andwaxes remain as liquids on the granules or particles. This can result insticking or non-uniform coating. The temperature will vary somewhat withthe different waxes and fats used in coating. Typically, the temperaturemay be from about 35 to about 40 C. It should be noted that the airpassing through, which volatilizes the solvent, will ordinarily bemaintained at a somewhat higher temperature, for example, from about 50to about 55 C., than that desired on the surface of the particlesbecause of the marked cooling effect resulting from the rapidevaporation of the solvent. The temperature of the air is thereforeadjusted to a sufficiently higher temperature than that desired on thesurface of the particles or granules. It is not possible to specifyexact air temperatures to be used in all cases because this is afifectedby the volume of air. A larger volume of air will be at a lowertemperature than a smaller volume of air. Once the air flow has beenestablished and the temperature determined, it remains constant and anefficient continuous manufacturing process results producing particleswhich are not cemented to gether by too liquid a coating and which havea smooth, continuous coating over their entire surface. The particlesmay then be tabletted either with or without other constituents orincorporated in capsules by conventional means.

The fats and waxes used to slow up release are the same fats and waxeswhich have been used heretofore in similar preparations. As far as theparticular coating materials are concerned, the present invention doesnot change prior practice. The fact that well known materials are usedis an advantage of the present invention as it is not necessary to learnnew techniques for handling new materials. Typical coating materials arehigh melting fats such as glyceryl monostearate or glyceryl distearate,waxes like beeswax, or waxy higher alcohols, and the like. Usually,carnauba wax is unsuitable alone but in blends it permits an accuratedegree of hardening, especially with drugs having emulsifyingproperties. Inasmuch as the present invention does not involve thedevelopment of new coating materials, it is not limited to anyparticular ones and any slowly dispersible waxes or digestible hard fatsmay be used.

Within the range of permissible toxicities, any volatile solvent for thefats and waxes may be used. In addition to the 1,1,l-trichlorethanementioned above, the following are suitable solvents: chloroform, carbontetrachloride, other volatile halogenated hydrocarbons, petroleum ether,etc.

The invention requires definite, though fairly wide, limits of particlesize of the granules or particles to be coated. The general range isfrom US. standard 12 mesh to U.S. standard 80 mesh. Particles coarserthan 12 mesh will not encapsulate or tablet satisfactorily. Anyconsiderable amount of particles finer than 80 mesh tend to clump. Ofcourse, minute amounts of fines resulting from an occasional brokengranule can be tolerated but any significant proportion of particlesfiner than mesh defeats the purpose of the present invention. In theclaims, the term substantially all being from 12 mesh to 80 mesh isintended to cover this situation and to have no other meaning. In thecase of citric acid in which the crystals are dense, it is desirable touse a slightly narrower range of from US. standard 16 mesh to US.standard 60 mesh. In fact, even with bulkier materials which can becoated up to about 80 mesh, the preferred particle size range is alsofrom 16 mesh to 60 mesh as this gives products of optimum properties.

It should be reiterated that the essence of the present invention liesin the non-uniform coating of non-uniform particle size material in asingle coating operation. It should not be confused with a physicalmixture of uneoated and uniformly coated material. The uncoated materialdoes, in fact, give a rapid initial release, the socalled attack dose,but there is not the uniform release thereafter over a period of hours,which is the important advantage of the present invention.

The invention will be described in greater detail in conjunction withthe following specific examples. All parts are by weight unlessotherwise specified.

Example 1 The powdered anticholinergic agent, tridihexethyl iodide(S-diethylamino-l-cyclohexyl-l-phenyl-1-propanol The powders weregranulated in a Hobart mixer using a mixture of 350 ml. of corn syrupand 300 ml. of a 20% solution of gum acacia in water. The moist mass wasthen screened on a Stokes oscillating granulator through a 10 meshscreen. The damp granules were then dried at F. in a warm air oven andrescreened through a 16 mesh screen, fines being removed by a 40 meshscreen.

This 16/40 mesh granulation was then coated in a conventional tabletcoating pan. A wax coating solution containing 2700 grams of glycerylmonostearate (substantially glycerine free) and 300 grams of whitebeeswax were dissolved in 10,500 ml. of 1,1,l-trichlorethane. A smallamount, 0.75 gram, of D and C Violet Dye No. 2 was added. The coatingmixture was heated and held at 60-70 C. and was sprayed onto thegranules from a conventional paint spray gun at lO-IS pounds per squareinch pressure, 1.5-2.0 cubic feet per minute air flow, and 0.04 inchfluid nozzle orifice. The spray pattern was cone shaped. Spraying wascontinued until the total wax content reached 44% which requiredapproximately four hours. During the spraying process, a cycle was usedwhereby the granules were sprayed for ten minutes and then were tumbledin a stream of warm air adjusted to maintain the temperature of thegranules at 35-40 C. for ten minutes. After spraying was completed, thegranules were tumbled in a stream of warm air for an additional fifteenminutes followed by tumbling in air at room temperature for thirtyminutes. The final coated granules were then sifted through a No. 12mesh screen to remove all clumped granules. The amount of glurrlilpedgranules constituted less than 2% of the entire atc The coated granuleswere lubricated with a 1% magnesium stearate and tabletted on a standardStokes tabletting machine with 11/32 inch flat face bevel tabletpunches. The average gross tablet weight was approximately 200milligrams and the final tablet had a honeycomb like physical appearancewith an attractive two-tone color of light and dark violet. Release wasdetermined by a standard method using artificial gastric juice andintestinal fiuid. After one hour, one-half of the gastric juice wasreplaced. A ter two hours and after three hours, all of the fluid wasreplaced with artificial intestinal fluid. This was repeated again afterfive and seven hours. t periodic intervals, a sample was removed and thepercent of medicament released was determined. The results were asfollows:

1 hour 14% released 2.5 hours 29% released 4.25 hours 62% released 6hours 82% released 8 hours 98% released The above indicates thatsatisfactory blood levels can be maintained for about ten to twelvehours with a single dose of medicament. Ordinarily, the medicament wouldbe given in one or two tablets, three or four times per day. Comparableblood levels were obtained by the tablet of the present invention with asingle does of one or two tablets upon arising.

To determine the relative amount of coating, another batch of granuleswith an average wax content of 29.7% was classified through suitablesieves and the wax contents of the various fractions were determined.The results were as follows:

20/30 mesh 22.1% wax 18/20 mesh 33.4% wax 16/18 mesh 34.8% wax.

Example 2 Six thousand grams of tetracycline was granulated with a 25%solution of corn syrup by the method described in Example 1. It was thenscreened on the oscillating granulator through a 12 mesh screen anddried with warm air at 140 F. After drying, the granules were rescreenedthrough a 16 mesh screen. The fines were removed by sifting on a 60 meshscreen.

Five thousand grams of the 16/60 mesh granulation was coated asdescribed in Example 1 using a coating solution with 18.9% of glycerylmonostearate, 2.1% of white beeswax and the balance1,1,1-trichlorethane. Clumps were separated by sieving through a 12 meshscreen and a portion of the sifted granules were tabletted on a Stokesmachine with 13/ 32 inch FFB punch to an average tablet gross weight of463 milligrams.

The tablets were then submitted to the digestion test as described inExample 1. The release was 18% after one hour and 80% after seven hours.

The balance of the granules were encapsulated in the conventionalmanner. The resulting capsules were submitt d to a standard release ratetest and showed satis factory continual release for a period of tenhours.

Example 3 18,000 gm. of the diuretic,acetazolamide(2-acetylamino-l,3,4-thiadiazole-5sulfonamide), wasgranulated with 3900 ml. of a 15% gelatin solution. The material wasthen screened through a Fitzpatrick comminuting machine, using a No. 4Ascreen at 1000 rpm. The resulting granules were dried in a warm air ovenat 140 F. for 15 hours. These granules were then sifted to obtain thosefiner than No. 16 mesh. The balance of the granules were forced througha No. 16 screen on an oscillating granulator. The fines were removedthrough a No. 60 mesh screen. All 16/60 mesh granules were combined.

Cine third of the above granules were set aside and the remainder coatedin two phases so as to contain 5% and 10% respectively of the followingwax mixture:

Parts Glyceryl monostearate 9 White beeswax 1 The wax was applied as a30% solution in 1,1,1-trichlorethane, as in Example 1. The coatedgranules were sifted through a No. 12 mesh screen to remove the clumps.The three phases were then mixed in equal proportions and encapsulatedin the conventional manner.

Another sample of 10% wax coated granules was compressed into tablets.

When tested, both products showed a sustained release for approximately9 hours.

Example 4 A granulation was prepared as follows:

Gm. Tridihexethyl chloride 5625 Hyoscyamine hydrobromide 35.01 Hyoscinehydrobrornide 2.205 Atropine sulfate 6.555 Dicalcium phosphate, USP 5582Acetazolamide 37,500

All of the powders except the acetazolamide, were mixed in a pony mixerand then screened on a Fitzpatrick comrninuting machine, using a N0. 80screen, at 2200 r.p.m. The resulting powder mix was granulated asfollows.

The powders were granulated with the following solution:

Ethyl-cellulose, cps gm 30 1,1,1-trichlorethane ml.. 3000 Isopropanol ml2200 Percent Uncoated granules 20 15% coated granules 15 35% coatedgranules 10 50% coated granules The above mixture of granules was thenmixed with the acetazolamide powder in the ratio of one part granules totwo parts powder, and encapsulated in the conventional manner. The fillwas equal to 400 mg, net, of the powder-granule mixture.

Exampe 5 A bath of granules was prepared exactly as in Example 4, exceptthat the coating material consisted of:

Parts Glyceryl monostearate 4.5 Glyceryl distearate 4.5 White beeswax 1The same prolonged release was obtained as in Example 4.

Example 6 Same as Example 4 except that the coating material consistedof:

Parts Glyceryl monostearate 6 Carnauba wax 3 White beeswax 1 The releasetime was slightly longer than in Example 4.

2 Example 7 A granulation was prepared as follows:

T ridihexethyl chloride kg 10 Dicalcium phosphate, USP kg 101,1,1-trichloroethane l 3.75 Isopropanol, 99% N.F l 3.75

The two powders were mixed by barrel rolling for 30 minutes. Theresulting blend was screened through a Fitzpatrick comminuting machineusing a No. 1 screen, at 5000 rpm. and barrel rolled for an additional30 minutes. The resulting powder was then granulated in a Stokes Model21H powder mixer using the mixture of 3.75 liters of isopropanol and3.75 liters of 1,1,1-trichloroethane. The resulting lumpy material wasplaced directly on trays and dried for 16 hours at 40 C. followed by 2hours at 50 C. in a forced air drying cabinet. The dried lumps were thensifted on a No. 16 screen to remove the granules and the remainingmaterial was forced through a No. 16 screen on a Stokes oscillatinggranulator. All of the 16 mesh material was combined and lubricated with1% magnesium stearate and sifted on a No. 60 mesh screen to remove thefiner particles. The following fractions were obtained:

Kg. 16/60 mesh gr 14 Minus 60 mesh powder 6 Six kg. of the 16/ 60 meshgranules was placed in a 16 inch coating pan and coated with fullyhydrogenated tallow to a content of 18.2% fat. The fatty material wasapplied as a 33% solution in 1,1,1-trichloroethane, utilizing thestandard spraying technique described in Example 1.

The coated granules were allowed to air dry on trays at 040% relativehumidity for 16 hours.

A screen analysis of the coated granules was performed with thefollowing results:

A blend was prepared of 5850 grams of the 16/60 mesh granules with 1540grams of the 60/80 mesh granules. The drug was mixed with 3500 grams ofcottonseed flour, 210 grams magnesium stearate, and 105 grams propyleneglycol. The mix was then encapsulated in gelatin capsules with anaverage fill weight of 321 mg. per capsule, corresponding to a contentof 81 mg. per capsule of the drug. It should be noted that the druggranules contain slightly over 25% fat. The capsules gave the'samedesirable release rate as described in the preceding examples.

Example 8 A methoxypromazine(2-methoxy-10-(3'-dimethylaminopropyl)phenothiazine) maleate granulationwas prepared as follows:

Gm. Methoxypromazine maleate 4000 Dicalcium phosphate 3000 Sucrose 1000Powdered acacia 400 The powders were blended and screened through aFitzpatrick comminuting machine at 5000 r.p.m., using a No. 1 screen.This powder was granulated with a 35% corn syrup solution (a total of1500 ml. of solution was used). The lumpy material was dried in acirculating air cabinet at 120 F. for 16 hours and then screened througha No. 16 mesh screen on an oscillating granulator. The fines wereremoved through a No. mesh screen. 6500 gm. of the 16/60 mesh granuleswere then coated as in Example 7 using a solution of:

Glyceryl monostearate gm 1170 White beeswax gm 130 Trichloroethane ml4000 The coated granules were sifted on a No. 12 mesh screen to removeclumps. 1500 gm. of 12/60 mesh uncoated granules were mixed with thecoated granules and then assayed for methoxypromazine maleate. Thegranules were encapsulated in a conventional manner. A release rate testwas performed and the observed curve provided a sustained release ofmedicament for 11 hours.

Example 9 Five hundred grams of granular calcium cyanamid was screenedthrough a No. 16 mesh screen and then sifted on a No. 60 mesh screen toremove the fines. 410 gm. of the 16/60 mesh granules were obtained andcoated in an 8 inch coating pan with the following solution:

Gm. Glyceryl monostearate 45 White beeswax 5 1,1,1-trichloroethane 175Example 10 A granulation of triamcinolone free alcohol was pre paredaccording to the following procedure:

Triamcinolone free alcohol 30 Dicalcium phosphate, USP 870 The powderswere blended and screened through a No. 20 mesh screen. Granulation wasaccomplished with an aqueous solution consisting of gm. sucrose and 30gm. acacia in 200 m1. of solution. The granules were dried and screenedas in Example 1.

Five hundred gm. of the 16/40 mesh granules were coated with a solutionconsisting of 45 gm. glyceryl monostearate and 5 gm. white beeswax in150 ml. of total solution, using the method outlined in Example 1.

The resulting granules were mixed with uncoated granules in the ratio of4 parts coated granules to 1 part uncoated granules, and thenencapsulated.

The resulting product produced a sustained release of triamcinolone fora period of approximately 10 hours.

Example 11 The procedure of Example 10 was repeated except that thetriamcinolone free alcohol was replaced with 60 gm. of theantihistamine, chlorpheniramine maleate. The resulting product, whentested, showed a sustained release over a 10 hour period.

Example 12 A ferrous fumarate granulation was prepared as follows:

Ferrous fumarate powder gm 25000 Corn syrup, 50% aq. soln ml 7800 Thepowder was granulated with the solution, by slowly adding the latter tothe former with slow agitation in a Stokes mixer. The resulting mass wasdried in a cabinet, on trays, with circulating air at C. for 16 hours.Screening was accomplished with a Stokes oscillating Example 13 Agranulation was prepared as follows:

Gm. Salicylamide 3080 ll-acetyl-p-aminophenol eff. Ca cine 286 Acaciapowder The powders were blended and screened. Granulation was achievedusing 1500 ml. of a 35% aqueous solution of corn syrup. The mass wasdried at 100 F. for 25 hours and then screened through a No. 16 meshscreen using a Stokes oscillating granulator. The resulting granulationwas sifted on a No. 60 mesh screen to remove the lines.

4200 gm. of the resulting 16/60 mesh granules were coated as in Example1, using a solution consisting of 450 gm. glyceryl monostearate and 50gm. white beeswax in 1200 ml. of hot (65 C.) 1,1,1-trichloroethane.

The resulting coated granules were sifted through a No. 12 screen toremove the clumps.

4500 gm. of the thus coated granules were blended with 1200 gm. ofuncoated granules and the material was encapsulated at 475 mg. percapsule. The resulting product produced a sustained release ofmedicaments for a period of hours.

Example 14 A granulation of trihexyphenidyl (3-(l-piperidyl)-lphenyl-l-cyclohexyl-l-propanol hydrochloride) was prepared by theprocedure of Example 10, starting by blending the following powders:

Trihexyphenidyl 30 Dicaleium phosphate, USP 870 The esulting productproduced a sustained release of trihexyphenidyl for a period ofapproximately 10 hours.

Example 15 A granulation of rnephenoxalonc (5(o-methoxyphenoxyrnethyl)-2-oxazolidinone) was prepared, starting byblending the following powders:

Mephenoxalone 10,000 Acacia powder 500 The powders were blended andscreened. Granulation was achieved using 4400 ml. of a 50% aqueoussolution of corn syrup. The resulting mass was dried at 110 F. forhours, followed by four hours at 150 F. The dried granulation was thenmilled through a Fitzpatrick comminuting machine, using a N0. 2 screen,at 2200 r.p.m.; and then was screened through a No. 12 mesh screen. Theresulting granulation was sifted on a No. mesh screen to remove thefines.

Six thousand grams of this 12/40 mesh granulation was then coated in aconventional 18 inch coating pan. A wax coating solution containing 525g. of glyceryl monostearate and 58 of white beeswax dissolved in 1950ml. of 1,1,1-trichloroethane was prepared. A small amount, 0.2 g., of D& C Yellow Dye No. 11 was added. The wax coating solution was heated andheld at 60 C. and was sprayed onto the granules from a conventionalpaint spray gun as in Example 1. During the spraying process, a cyclewas used whereby the granules were sprayed for 5 minutes at ml. perminute and then were tumbled in a stream of warm air at 50 C. for 5minutes. This alternatingcycle was continued until all of the coatingsolution had been consumed.

A blend was prepared of 1315 g. of the 12/40 mesh coated granules with293 g. of the 12/40 mesh uncoated granules and 8 g. of magnesiumstearate powder. The ingredients were blended by tumbling in a drum for10 minutes and then were encapsulated in gelatin capsules in aconventional manner with an average fill weight of 500 mg. per capsule.A release rate test was performed which demonstrated a sustained releaseof medicament over a period of approximately 10 hours.

Example 16 A granulation of the diuretic, acetazolarnide, was preparedas follows:

Acetazolamide kg 150 Granular gelatin kg. 3.85 Distilled water liters 44The gelatin was dissolved in the water and the resulting solution washeated to 65 C. The acetazolamide powder was granulated with the gelatinsolution in a conventional manner and then dried at F. for 8 hours. Theresulting granulation was then milled through a Fitzpatrick comminutingmachine, using a No. 4A screen, at 1000 r.p.m.; and then was screenedthrough a No. 12 mesh screen. The resulting granules were sifted on aNo. 60 mesh screen to remove the fines.

On hundred kilograms of this 12/60 mesh granulation was then coated in aconventional coating pan. A wax coating solution containing 10.125 kg.of glyceryl monostearate and 1.125 kg. of white beeswax dissolved in37.5 liters of 1,1,l-trichloroethane was prepared. To this solution wasadded 3 g. of D & C. Yellow Dye No. 11 and 1.5 g. of D & C Red Dye No.17. The wax coating solution was heated and held at 60 C. and wassprayed onto the granules from a conventional paint spray gun as inExample 1. During the spraying process, a cycle was used whereby thegranules were sprayed for 5 minutes at 750 ml. per minute and then weretumbled in a stream of warm air at 50 C. for 5 minutes. This alternatingcycle was continued until all of the coating solution had been consumed.

One hundred kilograms of the thus coated 12/ 60 mesh granules wereintimately mixed with 30 kg. of uncoated 12/60 mesh acetazolarnide, 1.3k of talc, and 0.65 kg. of magnesium stearate. The ingredients wereblended by barrel rolling and then encapsulated in gelatin capsules in aconventional manner with an average fill weight of 550 mg. per capsule.A release rate test was performed which demonstrated a sustained releaseof medicament over a period of approximately 10 hours.

Example 17 A blend was prepared of 10,000 g. of coated ferrous fumarategranules (prepared as in Example 12), 6,950 g. of a granular fecalsoftener (72% by weight of dioctyl sodium sulfosuccinate absorbed on 28%by weight of fumed silica aerogel), 215 g. of magnesium stearate, and254 g. of dried corn starch. Blending was accomplished by barrel rollingfor 45 minutes. The resulting blend was encapsulated in gelatin capsulesin a conventional manner with an average fill weight of 350 mg. percapsule. When tested, the capsules demonstrated a sustained release ofiron over a period of approximately 4 hours.

e r saw 1 Example 18 A granulation of meprobamate (2-methyl-2-n-propyl-1,3-propanediol dicarbarnate) was prepared as follows:

Gm. Meprobamate powder 400,000 Acacia powder 15,000 Corn syrup, U.S.P40,000

Distilled water, q.s.ad. 60,000 ml.

The granulating solution was prepared by heating the distilled water to60 C. and adding the acacia and corn syrup with rapid agitation until anopalescent solution was obtained. The meprobarnate powder was granulatedwith the granulating solution in a conventional manner and then dried.The resulting granulation was then milled through a Fitzpatrickcommiuuting machine, using a No. 4A screen, at 1,000 r.p.m.; and thenwas screened through a No. 16 mesh screen. The resulting granules weresifted on a No. 60 mesh screen to remove the fines.

Eighty kilograms of this 16/ 60 mesh granulation was then coated in aconventional coating pan. A wax coating solution containing 12,600 g. ofglyceryl monostearate and 1,400 g. of white beeswax dissolved in 35liters of 1,1,1- trichloroethane was prepared. The wax coating solutionwas heated and held at 55-65 C. and was sprayed onto the granules from aconventional paint spray gun as in Example 1. During the sprayingprocess, a cycle was used whereby the granules were sprayed for 5minutes at 750 ml. per minute and then were tumbled in a stream of warmair at 50 C. for 5 minutes. This alternating cycle was continued untilall of the coating solution had been consumed.

A blend was prepared of 50 kg. of the 16/60 mesh coated granules with 21kg. of the 16/ 60 mesh uncoated granules, 700 g. of magnesium stearate,and 700 g. of dried corn starch. The ingredients were blended bytumbling in a drum for minutes and then were encapsulated in gelatincapsules in a conventional manner with an average fill weight of 500 mg.per capsule. When tested, the capsules demonstrated a sustained releaseof meprobamate over a period of approximately 10 hours.

Example 19 A granulation was prepared; starting by blending thefollowing powders:

G. Dextroamphetamine sulfate 30,000 Dibasic calcium phosphate 44,000Acacia powder 3,700

The powders were blended in a Stokes mixer for minutes. Granulation wasachieved using 12,000 ml. of a aqueous solution of corn syrup, and theresulting mass was dried at 110 F. for 20 hours. The dried granulationwas then milled through a Fitzpatrick comminub ing machine, using a No.2 screen, at 2,200 r.p.m.; and then was screened through a No. 16 meshscreen. The resulting granulation was sifted on a No. 40 mesh screen toremove the fines.

Fifty-five kilograms of this 16/40 mesh granulation was then coated in aconventional coating pan. A wax coating solution containing 13,950 g. ofglyceryl monostearate and 1,550 g. of white beeswax dissolved in 40liters of 1,1,1-trichloroethane was prepared. The wax coating solutionwas heated and held at -65 C. and was sprayed onto the granules from aconventional paint spray gun as in Example 1. During the sprayingprocess, a cycle was used whereby the granules were sprayed for 5minutes at 750 ml. per minute and then were tumbled in a stream of warmair at 50 C. for 5 minutes. This alternating cycle was continued untilall of the coating solution had been consumed.

A blend was prepared of 235,930 g. of coated meprobamate granules(prepared as in Example 18), 133,820 g. of uncoated meprobamate granules(also prepared as 12 in Example 18), 38,190 g. of coateddextroarnphetamine sulfate, 14,220 g. of uncoated dextroamphetaminesulfate, 5,000 g. of fumed silica aerogel, 2,500 g. of dried cornstarch, and 31,120 g. of sugar-starch filler. The ingredients wereblended by barrel rolling and then encapsulated in gelatin capsules in aconventional manner with an average fill weight of 460 mg. per capsule.A release rate test was performed which demonstrated a sustained releaseof both meprobamate and dextroamphetamine over a period of approximately10 hours.

This application is a continuation-impart of my ca pending applicationSerial No. 812,794, filed May 13. 1959, now abandoned.

What is claimed is:

1. An oral pharmaceutical preparation having a prolonged releasecomprising a plurality of medicament granules, substantially all beingfrom 12 mesh to 80 mesh, each coated with a layer of water insoluble,partly digestible hydrophobic material, the thickness of coating varyingdirectly with particle size whereby in oral use the very fine granulesrapidly release their medicament and the granules of increasing sizerelease their medicament more and more slowly.

2. A product according to claim 1 in which the medicament comprisestetracycline.

3. A product according to claim 1 in which the medicament comprisestridihexethyl halide.

4. A product according to claim 1 in which the medicament comprisestridihexethyl halide and phenobarbital.

5. A product according to claim 1 in which the medicament comprisestridihexethyl halide and mixed belladonna alkaloids.

6. A product according to claim 1 in which the medicament comprises2-acety1amino-1,3,4-thiadiazole-S-sulfonamide.

7. A product according to claim 1 in which the medicament comprises5-(omethoxyphenoxymethyl)-2-oxazolidinone.

8. A product according to claim 1 in which the medicament comprises2-methyl-2-n-propyl-1,3-propanediol dicarbamate.

9. A product according to claim 1 in which the medicament comprises2-methyl-2-n-propyl-1,3-propanedio1 dicarbamate and dextroamphetaminesulfate.

10. A product according to claim 1 in which the medicament comprisesferrous fumarate.

11. A product according to claim 1 in which the medicament comprisesferrous fumarate and a fecal softener.

12. A product according to claim 1 in which the medicament comprisescalcium cyanamide.

13. A product according to claim 1 in which the dicament comprisestrihexyphenidyl.

14. A product according to claim 1 in which the dicament comprisestriamcinolone free alcohol.

15. A product according to claim 1 in which the dicament comprisesmethoxypromazine maleate.

16. An oral pharmaceutical preparation having a prolonged releasecomprising a plurality of medicament granules, substantially all beingfrom 16 mesh to mesh, each coated with a layer of water insoluble,partly digestible hydrophobic material, the thickness of coating varyingdirectly with particle size whereby in oral use the very fine granulesrapidly release their medicament and the granules of increasing sizerelease their medicament more and more slowly.

17. A method of making oral pharmaceutical preparations having aprolonged medicament release which comprises sizing granules ofmedicament to produce a mixture having granules substantially all beingfrom 12 mesh to mesh, and spraying them with a solution in a volatilesolvent of water insoluble, partially digestible hydrophobic materialswhereby the granules are coated with a coating of the hydrophobicmaterial, increasing in thickness with increased particle size.

18. A method according to claim 17 in which the volatile solvent is1,1,1-trichloroethane.

19. A method of making oral pharmaceutical preparations having aprolonged medicament release which comprises sizing granules ofmedicament to produce a mixture having granules substantially all beingfrom 16 mesh to 60 mesh, and spraying them with a solution in a volatilesolvent of water insoluble, partially digestible hydrophobic materialswhereby the granules are coated with a coating of the hydrophobicmaterial, increasing in thickmess with increased particle size.

20. A method according to claim 19 in which the volatile solvent is1,1,1-trichloroethane.

References Cited in the file of this patent UNITED STATES PATENTS

1. AN ORAL PHARMACEUTICAL PREPARATION HAVING A PROLONGED RELEASECOMPRISING A PLURALITY OF MEDICAMENT GRANULES, SUBSTANTIALLY ALL BEINGFROM 12 MESH TO 80 MESH, EACH COATED WITH A LAYER OF WATER INSOLUBLE,PARTLY DIGESTIBLE HYDROPHOBIC MATERIAL, THE THICKNESS OF COATING VARYINGDIRECTLY WITH PARTICLE SIZE WHEREBY IN ORAL USE THE VERY FINE GRANULESRAPIDLY RELEASE THEIR MEDICAMENT AND THE GRANULES OF INCREASING SIZERELEASE THEIR MEDICAMENT MORE AND MORE SLOWLY.